Therapeutic vascular occlusion (embolization) is a technique used to treat pathological conditions in situ by injection of an occlusion agent (embolic material) into a vessel. Embolization is carried out by means of catheters, making it possible to position particulate occlusion agents or gels (emboli) in the circulatory system. In active embolization therapy, embolic agents are formulated with therapeutic agents, such as a drug or chemotherapeutic, resulting in both mechanical blockage and in situ delivery of the therapeutic agent. The use of embolization in cancer therapy has also been established. For example, blood vessels which nourish cancerous tumors are deliberately blocked by injection of an embolic material into the vessel. Vascular occlusion can limit blood loss during the surgical interventions, and contribute to tumoral necrosis and recession. Combining the occlusion agent with a chemotherapeutic can allow delivery of the chemotherapeutic directly to the tumor without significant systemic deliverly, which allows higher doses of chemotherapeutic to be used.
Transarterial embolization (TAE) or transarterial chemoembolization (TACE) have been used extensively to treat patients with hypervascular tumors confined to the liver or tumors where the intrahepatic component is the main source of mobidity and mortality. TAE/TACE are considered effective palliative care for unresectable tumors or as an adjuvant to manage postoperative recurrent tumors (Camma et al, (2002) Radiology, 224:47-54; Llovet et al., (2002) Lancet 359:1734-1739; Jelic et al., (2010) Ann Oncol. 21 Suppl 5:v59-v64). Various embolization agents and chemotherapeutics have been used, although clear superiority for any particular regimen or chemotherapeutic has not been demonstrated (Nakamura et al., (1994) Cancer Chemother Pharmacol 33 Suppl:S89-S92; Bruix et al., (2004) Gastroenterology 127:S179-S188).
In parallel, oncolytic viruses are in development for treatment of cancer. For example, replication-selective oncolytic viruses hold promise for the treatment of cancer (Kim et al., (2001) Nat. Med., 7(7):781-787). These viruses can cause tumor cell death through direct replication-dependent and/or viral gene expression-dependent oncolytic effects (Kirn et al., (2001) Nat. Med., 7(7):781-787). In addition, viruses are able to enhance the induction of cell-mediated antitumor immunity within the host (Todo et al., (2001) Cancer Res., 61:153-161; Sinkovics et al., (2000) J. Clin. Viro., 16:1-15). These viruses also can be engineered to expressed therapeutic transgenes within the tumor to enhance antitumor efficacy (Hermiston, (2000) J. Clin. Invest., 105:1169-1172).
However, major limitations exist to this therapeutic approach. Although a degree of natural tumor-selectivity can be demonstrated for some virus species, new approaches are still needed to engineer and/or enhance tumor-selectivity for oncolytic viruses in order to maximize safety and efficacy. This selectivity is particularly important when intravenous administration is used, and when potentially toxic therapeutic genes are added to these viruses to enhance antitumor potency; gene expression will need to be tightly limited in normal tissues. In addition, increased antitumor potency through additional mechanisms such as induction of antitumor immunity or targeting of the tumor-associated vasculature is highly desirable. Therefore, more effective and less toxic therapies for the treatment of cancer are needed.
Initial attempts to combine oncolytic viral therapy with embolization have been made. An oncolytic form of vesicular stomatitis virus (VSV) has been tested in tumor models (Altomonte et al. (2008) Hepatology 48:1864-1873). VSV was an ideal candidate to test with embolization. VSV, a member of the rhabdoviridae family, is a negative-sense RNA virus 180 nm long and 75 nm wide. VSV enters and is released from the basolateral surfaces of polarized cells. The basolateral release of VSV allows it to readily infect underlying tissues, including tumor tissues (Basak et al., (1989) J. Virology, 63(7):3164-3167). In addition, the small size of VSV, particularly the 75 nm diameter of its smallest axis, allows its passage through the leaky junctions between blood vessel cells, allowing the infection of underlying tissues and through the basolateral surface of the blood vessel cells. Due to its small size and basal surface budding, one of skill in the art could have expected successful infection of tumor tissue during viral embolization of VSV.
Given the ideal characteristics of VSV, it is difficult to extrapolate other oncolytic viruses. For example, viruses that that have a diamerter along their smallest axis that is larger than the junctions between cells of blood vessels may not be able to pass from the blood stream to the surrounding issue. Similarly, viruses that release from the apical side of polar cells are typically limited to infection along epithelial cell linings (Basak et al. (1989) J. Virology, 63(7):3164-3167). When such a virus infects a polar endothelial blood vessel cell, the replicated viruses could simply be released back into the blood stream rather than into the underlying tissue if released apically. Vaccinia virus is an example of a virus that has a number of undesirable characteristics that could have been expected to prevent effective embolization. Vaccinia virus (VV), a member of the poxvirus family, is a large virus roughly 360 nm by 250 nm in size. Vaccinia virus preferentially infects through the basolateral surface of polar cells, but its viral progeny are released from the apical surface (Vermeer et al., (2007) J. Virology, 81(18):9891-9899). A virus that is apically released from the polar endothelial cells that create the blood vessel waslls is thus at risk of being washed away by the blood stream. In addition, due to its large size, vaccinia virus would have difficulty passing through cellular junctions between cells of the blood vessel walls to reach to the basolateral surface of the endothelial cells and subsequently infect underlying tissues in any substantial amount. Based upon its lifecycle and size, one could not extrapolate from the VSV results to oncolytic vaccinia virus, or other large viruses or viruses that release from the apical surface for that matter, being able to achieve significant penetration into a tumor during vascular embolization.
All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety.